This application addresses the broad Challenge Area (08) Genomics, Beyond GWAS 08-DK-102. The overall genetic architecture and pathogenic mechanisms of complex disorders such as Crohn's disease (CD) is incompletely defined at present. Genome-wide association studies (GWAS) have identified over 30 genetic loci that are definitively associated with CD. The large number of genomic loci which have been associated with CD only account for approximately 20% of the genetic variance contributing to disease. A fundamental challenge in complex disorders is attempting to determine the nature and sources of this "missing heritability." The resulting challenge for complex geneticists is to comprehensively define the overall genetic architecture of a particular disease. This proposal goes beyond single-point GWAS analyses to identify uncommon variation contributing to disease through haplotype analysis of GWAS data. We propose to leverage one of the major, genetic resources in Crohn's disease genetics, namely, the Ashkenazi Jewish population. The significantly higher disease prevalence, familial relative risk and endogamy observed in this cohort suggest that focused studies here would be particularly fruitful. The association signals thus far established in primarily non-Jewish European ancestry GWAS do not account for the higher disease prevalence observed among Ashkenazi Jews, suggesting that alternative methodologic approaches should be attempted, which forms the basis of this challenge grant application. Specific Aim #1 will sequence genes within shared haplotypes identified in Ashkenazi Jewish Crohn's disease populations in order to identify highly pathogenic and protective genetic variation. We present data demonstrating a greater than expected number of uncommon haplotype regions demonstrating association to Crohn's disease in Jewish, but not non-Jewish Crohn's disease. Sequencing of genes in these regions may identify uncommon variation associated with Crohn's disease. An efficient pooling strategy leveraging shared haplotype cohorts and high throughput sequencing is proposed. Specific Aim #2 will define the role of genetic variation identified in Aim #1 in the overall genetic architecture of Crohn's disease and ulcerative colitis. The gene- based variants identified in Specific Aim #1 will be tested through individual genotyping of Jewish and non-Jewish case-control cohorts, as well as genotype the GWAS markers that comprise the associated haplotype, to establish the role of these uncommon variants in the overall architecture of Crohn's disease. PUBLIC HEALTH RELEVANCE: Crohn's disease is a chronic inflammation of the intestines and genetic scans of the entire genome have been extremely successful in identifying common genetic variation that is associated with disease. However, a major challenge is to identify less common variation that may provide additional insight into disease mechanisms and potential therapies applicable to select subsets of individuals affected by these disorders.